SMA THERAPIES II AND BIOMARKERS: P.257JEWELFISH: RG7916 increases SMN protein in patients with SMA that have previously received therapies targeting SMN2 splicing

Abstract

Spinal muscular atrophy (SMA) is characterized by motor neuron loss and muscle atrophy due to reduced levels of survival of motor neuron (SMN) protein from loss of function of the SMN1 gene. While SMN1 produces full-length SMN protein, a second gene, SMN2, produces only low levels of functional SMN protein. RG7916 (RO7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates SMN2 pre-mRNA splicing towards the production of full-length SMN2 mRNA, resulting in an increase of SMN protein. JEWELFISH (NCT03032172) is a multicenter, open-label, exploratory study evaluating the safety, tolerability and pharmacokinetics of daily oral RG7916 in patients with SMA type 2 or 3, aged 12-60 years, who previously participated in a study with therapies targeting SMN2 splicing. The pharmacodynamic (PD) effects on SMN2 mRNA and SMN protein are also being assessed. The study will soon be expanded to include patients >6 months of age with all SMA Types. At abstract submission, 11 patients in JEWELFISH with type 2 or 3 SMA have received RG7916 for a minimum of 3 weeks, and up to 13 months. To date, no drug-related adverse events leading to withdrawal have been reported. Preliminary PD data in whole blood from 10 patients receiving RG7916 showed an up to 4-fold SMN protein increase versus baseline after 4 weeks of treatment. While the patient number in JEWELFISH is limited, the magnitude of the SMN protein increase and the safety observations thus far are comparable to what has also been observed in the SUNFISH Part 1 study (NCT02908685) in type 2 and 3 patients who have not previously received an SMN2-targeting therapy. A JEWELFISH update, including safety and PD data, will be presented. The JEWELFISH study is currently recruiting in sites in Europe and the US.